Iontophoresis is the transport of ionized or charged species by application of an electrical current. Transdermal iontophoresis is the transport of an ionic drug through the skin of a mammal, usually a human, by passing a current through a drug-containing electrode placed against the skin. A second electrode, termed the return or indifferent electrode, is placed against the skin, normally several inches from the first. The current is evoked by applying a potential between the electrodes in a constant DC, pulsed DC or AC mode. The current carries the ionized drug "through" the stratum corneum into the dermis where the drug diffuses into the capillaries situated near the dermalepidermal junction, and then into the systemic circulation.
During clinical trials and animal experiments of drugs which increase heart rate and are therefore effective as exercise simulating agents, it was observed that after transdermal iontophoretic administration of the drug the time required to return the elevated heart rate to or near the normal, or baseline heart rate was not as fast as desired.
Although the present invention has general application in virtually all circumstances where a drug is administered iontophoretically, the primary intended uses are in conjunction with administration of certain exercise simulating agent (ESA .TM.) drugs on human patients, as described in several commonly assigned and co-pending patent applications. For this reason additional background will be provided concerning these exercise simulating agent drugs and the delivery systems, including the electrodes, preferably used.
Exercise simulating agents are drugs that elicit acute and adaptive cardiovascular responses similar to the types of responses elicited by aerobic activity. They are particularly useful, therefore, as a substitute for exercise stress testing for diagnosing cardiovascular diseases, due to their ability to increase heart rate, myocardial contractility, arterial blood pressure, and coronary and skeletal muscle blood flow. Exercise simulating agents of sufficient potency and iontophoretic mobility can be advantageously delivered, i.e., transported through the stratum corneum, using iontophoresis.
The amount of drug transported into the skin per unit time per unit area is known as the flux. Flux is proportional to the applied electrical potential and the drug concentration on the outside of the skin. The upper limit of current density to ensure that the current will not damage the skin is generally considered to be 0.5 mAmp/cm.sup.2 of DC current. Other limits on flux include drug solubility, the partition coefficient of drug in the stratum corneum, and the drug's iontophoretic mobility. Clinically effective transdermal iontophoresis must be achieved within these limits on the flux.
In addition to the above-listed factors, the flux is greatly affected by several other factors. For example, the drug's ability to pass freely, i.e., its mobility often depends on the pH of the solution in which it is delivered, and optimum iontophoretic mobility requires that the drug be ionized or in charged form at some specific pH. Also, reduced iontophoretic efficiency, i.e., lower flux of a given drug, can result from the presence of other ionic species in the formulation. These other ions will "compete" with the drug ions as current carriers and can drastically reduce iontophoretic flux.
Known problems associated with iontophoretic delivery of drugs include electrical or chemical burns, dermal irritation, incompatibility between the drug and other excipients in the drug-containing medium, slow onset of pharmacologic activity and lack of drug delivery response to application and removal of current, drug degradation due to anodic current flow, pH change, and unsatisfactory drug storage capability. The present invention addresses several of these problems in order to help achieve safer, more reliable and more convenient medical transdermal iontophoresis.
Regarding the specific electrodes useful in conjunction with the present invention three have been specifically proposed for transdermal iontophoresis, these being classified as: (1) monolithic pad; (2) reservoir pad; and (3) multilayer pad. All three may be used in conjunction with the present invention.
A monolithic electrode pad design provides for including the drug in a polymer or matrix that is attached to the electrode. The polymer may contain an adhesive to maintain contact with the patient's skin. The drug is dispersed in the polymer during manufacture and the polymer is then formed into the pad itself. An example of the class of polymers suitable for use in such pads are hydrogels, for example, poly(hydroxy ethyl methacrylate) (HEMA).
A reservoir electrode pad design allows for addition of the drug to an electrode which includes a disk and which is attached to the patient's skin. In such a design, the drug is contained in a reservoir or cavity formed during the manufacture of the electrode. The drug can be added in gel form during manufacture of the pad, after its manufacture, or immediately prior to use to form the drug-containing matrix.
A multilayer electrode pad includes separate layers for a buffering solution, an ion-exchange membrane and a drug reservoir.
Regardless of the design of the drug delivery electrode pad, the pad itself may be of any shape, but it should conform to the area of the body where it is applied. The size of the pad may be up to about 20 cm.sup.2, but preferably is only as large as required to keep current density below 0.5 mAmp/cm.sup.2. Although not fully understood, reduced current density may be a major factor in avoiding pH changes, damage to the patient's skin and build up of drug in a depot, or region in the dermis.
If the drug-containing matrix itself has no buffering capacity, the electrode material should include a material that undergoes an oxidation reduction reaction, such as silver/silver chloride, zinc/zinc chloride, or carbon-filled electrodes. It may be desirable to add a small amount of buffer, e,g., citrate or phosphate buffer, to maintain the desired pH in the electrode.
The gel may comprise a soluble polyHEMA, such as hydroxyethylmethacrylate available from Benz Research; hydroxypropylmethyl cellulose sold as Methocel.TM., ElOM, by Dow Chemical or Carbopol available as 934P, from B. F. Goodrich, and may include a preservative to prevent microbial growth. Parabens, such as methyl, ethyl and propyl are preferred preservatives. Small amounts of EDTA as a chelating agent may be included. Preferred gels also include an antioxidant to prevent oxidation due to the drug-electrode interaction. Preferred antioxidants include sodium bisulfite and vitamin C. The solvent for the gel may comprise deionized, pyrogen-free water or polyethylene glycol, such as PEG 400, 10-20%. If desired, ethanol, 100%, may be added as a co-solvent. The concentration of the drug within the gel is preferably in the range of approximately 5-25 mg/ml.
Prior to placing the drug delivery electrode pad on the skin of the patient, it may be desirable for the technician or doctor to abrade the skin using a clinically acceptable tape material or other method. This removes part of the stratum corneum, the main barrier to transport of the drug into the dermis. Permeation enhancers may be applied topically prior to applying the drug delivery electrode pad to increase the flow of the drug through the stratum corneum. Preferred permeation enhancers include surfactants such as sodium lauryl sulfate.
As described in more detail in application Ser. No. 308,683, filed Feb. 9, 1989, the preferred system used for delivery of the ESA .TM. drug includes a conventional power source operatively connected to the subject, typically a human, and having the capability to control or regulate the rate at which the drug is administered. The system also includes a conventional electrocardiographic monitoring device connected to the subject and a conventional microprocessor operatively connected to both the power source and the electrocardiographic monitoring device so that heart rate, changes in heart rate and drug delivery may be monitored, displayed and controlled or regulated.
Consistent with the above background and for the purpose of more fully understanding the primary expected uses of the present invention, several commonly assigned and co-pending applications directed to specific ESA" drugs and systems are incorporated herein by reference. These applications are listed as follows:
U.S. patent application Ser. No. 308,683, filed Feb. 9, 1989, is directed to the diagnosis, evaluation and treatment of coronary artery disease by exercise simulation using a closed loop drug delivery of an exercise simulating agent beta agonist by iontophoresis;
U.S. patent application Ser. No. 471,296, filed Jan. 26, 1990, is directed to an apparatus and method for iontophoretic transfer of drugs; and
U.S. patent application Ser. No. 471,178, filed Jan. 26, 1990, is directed to an iontophoretic transfer electrode and a method of transdermal drug delivery.
All of these applications are directed to iontophoretic delivery of certain drugs known as exercise simulating agent beta agonists (hereinafter referred to as "exercise stimulating agents", ESA" Beta Agonists or ESA" drugs).
Reference is also made herein to other publications. All such publications referred to herein are incorporated by reference and are listed in the Bibliography which immediately precedes the claims.